RESUMEN
OBJECTIVE: To investigate the safety, tolerability, pharmacokinetics, and efficacy of apilimod mesylate, an oral interleukin-12 (IL-12)/IL-23 inhibitor, in patients with rheumatoid arthritis (RA). METHODS: We performed a phase IIa, randomized, double-blind, placebo-controlled proof-of-concept study of apilimod, in combination with methotrexate, in 29 patients with active RA (3:1 ratio of apilimod-treated to placebo-treated patients) in 3 stages. Patients received apilimod 100 mg/day or placebo for 4 weeks (stage 1) or 8 weeks (stage 2). In stage 3, patients received apilimod 100 mg twice a day or placebo for 8 weeks, with an optional extension of 4 weeks. Clinical response (Disease Activity Score in 28 joints [DAS28] and American College of Rheumatology [ACR] criteria) was assessed throughout; synovial tissue samples collected at baseline and on day 29 (stages 1 and 2) or day 57 (stage 3) were stained for cellular markers and cytokines for immunohistochemistry analysis. RESULTS: While only mild adverse events were observed in stages 1 and 2, in stage 3, all patients experienced headache and/or nausea. Among apilimod-treated patients (100 mg/day), there was a small, but significant, reduction in the DAS28 on day 29 and day 57 compared with baseline. ACR20 response was reached in only 6% of patients on day 29 and 25% of patients on day 57, similar to the percentage of responders in the placebo group. Increasing the dosage (100 mg twice a day) did not improve clinical efficacy. Consistent with clinical results, apilimod did not have an effect on expression of synovial biomarkers. Of importance, we also did not observe an effect of apilimod on synovial IL-12 and IL-23 expression. CONCLUSION: Our results do not support the notion that IL-12/IL-23 inhibition by apilimod is able to induce robust clinical improvement in RA.
Asunto(s)
Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Interleucina-12/antagonistas & inhibidores , Interleucina-23/antagonistas & inhibidores , Morfolinas/uso terapéutico , Triazinas/uso terapéutico , Adulto , Anciano , Antirreumáticos/efectos adversos , Antirreumáticos/farmacocinética , Método Doble Ciego , Quimioterapia Combinada , Femenino , Humanos , Hidrazonas , Masculino , Metotrexato/efectos adversos , Metotrexato/uso terapéutico , Persona de Mediana Edad , Morfolinas/efectos adversos , Morfolinas/farmacocinética , Pirimidinas , Resultado del Tratamiento , Triazinas/efectos adversos , Triazinas/farmacocinéticaRESUMEN
Inflammation of synovium is one of the hallmarks of rheumatoid arthritis (RA). Analysis of synovial tissue has increased our understanding of RA pathogenesis, aided in identifying potential therapeutic targets and has been used in the response and mechanistic evaluation of antirheumatic treatments. In addition, studies are ongoing, aimed at the identification of diagnostic and prognostic biomarkers in the synovium. This paper outlines the currently used procedures for sampling and processing of synovial tissue, and presents a standardised recommendation to support multicentre translational research.
Asunto(s)
Antirreumáticos/uso terapéutico , Artritis Reumatoide/patología , Biopsia/métodos , Membrana Sinovial/patología , Sinovitis/patología , Artritis Reumatoide/tratamiento farmacológico , Artroscopía/métodos , Biopsia/normas , Ensayos Clínicos como Asunto/normas , Humanos , Articulación de la Rodilla/patología , Estudios Multicéntricos como Asunto/normas , Resultado del Tratamiento , Ultrasonografía Intervencional/métodosRESUMEN
PURPOSE: Radiotherapy is commonly used to treat the majority of patients with head and neck cancers. Salivary glands in the radiation field are dramatically affected by this procedure. The purpose of this study was to examine pharmacokinetic characteristics of the stable nitroxide 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (tempol) with respect to radioprotection of the salivary glands. EXPERIMENTAL DESIGN: To evaluate the effect of different doses and times of administration, the heads of C3H mice were exposed to a single irradiation dose of 15 Gy, with i.p. tempol injection. To analyze other routes of administration, we injected 275 mg/kg tempol by an i.m., i.v., or s.c. route, 10 minutes before irradiation. We also tested whether oral administration of tempol in a topical form (either in a mouthwash or gel) provided any salivary gland protection. RESULTS: Tempol treatment (137.5 or 275 mg/kg, i.p., 10 minutes before irradiation) significantly reduced irradiation-induced salivary hypofunction (approximately 50-60%). I.v. or s.c. administration of tempol also showed significant radioprotection, whereas i.m. administration proved to be ineffective. Topical use of tempol, either as a mouthwash or gel, also was radioprotective. CONCLUSIONS: Our results strongly suggest that tempol is a promising candidate for clinical application to protect salivary glands in patients undergoing radiotherapy for head and neck cancers.
Asunto(s)
Irradiación Craneana/efectos adversos , Óxidos N-Cíclicos/farmacocinética , Protectores contra Radiación/farmacocinética , Xerostomía/prevención & control , Animales , Óxidos N-Cíclicos/administración & dosificación , Vías de Administración de Medicamentos , Femenino , Inyecciones Intraperitoneales , Inyecciones Subcutáneas , Ratones , Ratones Endogámicos C3H , Modelos Animales , Protectores contra Radiación/administración & dosificación , Glándulas Salivales/efectos de los fármacos , Glándulas Salivales/patología , Glándulas Salivales/efectos de la radiación , Salivación/efectos de los fármacos , Salivación/efectos de la radiación , Marcadores de Spin , Xerostomía/etiología , Xerostomía/metabolismoRESUMEN
Female nonobese diabetic (NOD) mice develop spontaneous autoimmune sialadenitis and loss of salivary flow, and are a widely used model of Sjögren's syndrome. We examined the feasibility of local salivary gland immunomodulatory gene delivery to alter these sequelae in NOD mice. We constructed recombinant adeno-associated virus (rAAV) vectors encoding either human interleukin 10 (rAAVhIL-10) or beta-galactosidase (rAAVLacZ, control vector). Mice received rAAVhIL-10 or rAAVLacZ by retrograde submandibular ductal instillation either at age 8 weeks (early, before onset of sialadenitis), or at 16 weeks (late, after onset of sialadenitis). As a systemic treatment control, separate mice received intramuscular delivery of rAAVhIL-10 at each time point. Both submandibular and intramuscular delivery of vector led to low circulating levels of hIL-10. After submandibular administration of rAAVhIL-10, salivary flow rates at 20 weeks for both the early and late treatment groups were significantly higher than for both rAAVLacZ-administered and untreated mice. Systemic delivery of rAAVhIL-10 led to improved salivary flow in the late treatment group. Inflammatory infiltrates in submandibular glands, however, were significantly reduced only in mice receiving rAAVhIL-10 locally in the salivary gland compared with mice receiving this vector intramuscularly, or rAAVLacZ or no treatment. In addition, after submandibular rAAVhIL-10 delivery, NOD mice exhibited significantly lower blood glucose, and higher serum insulin, levels than all other groups, indicating some systemic benefit of this treatment. These studies show that expression of hIL-10 by rAAV vectors can have disease-modifying effects in the salivary glands of NOD mice, and suggest that local immunomodulatory gene transfer may be useful for managing the salivary gland pathology in Sjögren's syndrome.
Asunto(s)
Dependovirus/genética , Técnicas de Transferencia de Gen , Interleucina-10/genética , Síndrome de Sjögren/terapia , Animales , Línea Celular , ADN Complementario/metabolismo , Modelos Animales de Enfermedad , Femenino , Vectores Genéticos , Humanos , Interleucina-10/metabolismo , Ratones , Ratones Endogámicos NOD , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Glándulas Salivales/metabolismo , Factores de TiempoRESUMEN
Clinical applications of gene transfer technology initially targeted the treatment of inherited monogenetic disorders and cancers refractory to conventional therapies. Today, gene transfer approaches are being developed for most tissues and for multiple disorders including those affecting quality of life. The focus herein is eventual application of gene transfer technology for the management of organ-directed autoimmunity. A specific example is presented: Sjögren's syndrome and localized salivary gland gene transfer. The status of relevant pre-clinical gene transfer studies is reviewed, with an emphasis on use of adenoviral and adeno-associated viral vectors. Current limitations of effective organ-directed gene transfer are also discussed.
Asunto(s)
Técnicas de Transferencia de Gen , Terapia Genética/métodos , Vectores Genéticos/genética , Adenoviridae/genética , Ensayos Clínicos como Asunto , Técnicas de Transferencia de Gen/tendencias , Humanos , Síndrome de Sjögren/genética , Síndrome de Sjögren/terapiaRESUMEN
Personalised medicine has the potential to increase therapeutic effectiveness, reduce side effects and lower cost. This approach has recently taken off in oncology where different malignancies may be treated with specific drugs based on genetic biomarkers or other tumour characteristics. This type of tailored therapy could also be developed for immune-mediated inflammatory disease, for which rheumatoid arthritis (RA) may serve as a prototype. While novel treatments are able to halt or even prevent disease progression, not all RA patients respond, and stratification of patient groups is needed. The identification of biomarkers predictive of the clinical response to specific treatments in subsets of patients may soon become reality in a variety of diseases.
Asunto(s)
Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Anticuerpos Monoclonales/economía , Anticuerpos Monoclonales/uso terapéutico , Antirreumáticos/economía , Artritis Reumatoide/economía , Biomarcadores , Análisis Costo-Beneficio , Progresión de la Enfermedad , Humanos , Pronóstico , Años de Vida Ajustados por Calidad de Vida , Receptores del Factor de Necrosis Tumoral/administración & dosificación , Receptores del Factor de Necrosis Tumoral/uso terapéutico , Resultado del TratamientoRESUMEN
BACKGROUND: Non-obese diabetic (NOD) mice exhibit autoimmune diabetes and Sjögren's-like syndrome. OBJECTIVE: To test whether a treatment that reverses end-stage diabetes in the NOD mouse would affect their Sjögren's-like syndrome. METHODS: NOD mice have a proteasome defect. Improperly selected naive T cells escape, but can be killed by reintroducing major histocompatibility complex class I self-peptides on matched normal splenocytes. The proteasome defect also impairs nuclear factor kB, a transcription factor in pathogenic memory T cells, increasing their susceptibility to tumour necrosis factor-induced apoptosis stimulated through complete Freund's adjuvant (CFA). The impact of this two-limb therapy (injections of matched normal splenocytes and CFA) on the autoimmune salivary gland disease of the NOD mice was studied. RESULTS: All NOD mice receiving the above treatment had a complete recovery of salivary flow and were protected from diabetes. Restoration of salivary flow could be the result of a combination of rescue and regeneration of the gland, as confirmed by immunohistochemical analysis. All untreated NOD mice showed a continuous decline in salivary flow, followed by hyperglycaemia and death. CONCLUSION: This study establishes that a brief intervention in NOD mice with Sjögren's-like syndrome can reverse salivary gland dysfunction.
Asunto(s)
Enfermedades Autoinmunes/terapia , Diabetes Mellitus Experimental/terapia , Síndrome de Sjögren/terapia , Animales , Enfermedades Autoinmunes/fisiopatología , Diabetes Mellitus Experimental/complicaciones , Modelos Animales de Enfermedad , Femenino , Adyuvante de Freund , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Glándulas Salivales/fisiopatología , Salivación , Tasa de Secreción , Síndrome de Sjögren/complicaciones , Síndrome de Sjögren/fisiopatología , Bazo/trasplanteRESUMEN
Chong et al., Nishio et al., and Suri et al. (Reports, 24 March 2006, pp. 1774, 1775, and 1778) confirmed that treating nonobese diabetic (NOD) mice with an immune adjuvant and semisyngenic spleen cells can reverse the disease but found that spleen cells did not contribute to the observed recovery of pancreatic islets. We show that islet regeneration predominately originates from endogenous cells but that introduced spleen cells can also contribute to islet recovery.